The overall aim of the proposed research is to study peptide hydrolysis within serine proteases by using novel density functional theory based mixed quantum-classical methodologies. Mixed quantum-classical methods are necessary to model chemical reactions in which there is bond breaking and formation. We propose to approach the problem in a stepwise fashion, breaking it down into relevant components. Specific aim 1 plans to test various mixed quantum-classical potentials in their ability to adequately represent interactions within a peptide. In specific aim 2 we propose to calculate a likely reaction pathway for ester hydrolysis. In doing so the structural changes that occur during the reaction will be investigated and analyzed. Then using information gained in both Specific Aims 1 and 2, the reaction will be modeled in a chymotrypsin enzyme mimic and in chymotrypsin itself. In this way much more will be learned regarding the role of the active site in peptide hydrolysis. These calculations are made possible, not only with the mixed quantum-classical methods but also through newly developed and efficient sampling algorithms to study complex biological reactions.